February 13, 2018
CBC-sponsored researchers discover a potential Epstein–Barr virus (EBV) receptor—the Longnecker lab, NU, in a spotlight
Using a clever bioinformatics approach to subtract the gene expression profile of epithelial cells susceptible to EBV infection from that of the cells resistant to the infection, the Longnecker lab at NU identified Ephrin receptor A2 as a functional entry receptor for the virus. The study opens doors to deciphering the exact mechanisms of the virus entry and to the development of targeted treatments to prevent it. Published in the February issue of Nature Microbiology, the study is partially attributed to the CBC funding to Richard Longnecker and his postdoctoral fellow, Jia Chen, through the CBC 2014 Postdoctoral Research Award (PDR) and its renewal for 2015. Chen is first author on the publication. Longnecker, who is senior author on the paper, has strong ties to the CBC: he was a member of the CBC Scientific Recruitment Board (2007-2012) and a recipient of CBC Catalyst Award (2012). Another co-author on the study, Bethany Perez White is also a past CBC PDR Award recipient (2014 & 2015 renewal). Congratulations to all involved in the research!
Untangling How Epstein-Barr Virus Infects Cells
Northwestern Medicine News Center | by Will Doss | January 9, 2018
Richard Longnecker, PhD, the Dan and Bertha Spear Research Professor, was the senior author of the study published in Nature Microbiology.
A team led by scientists at Northwestern Medicine has discovered a new epithelial receptor for Epstein-Barr virus, according to a study published recently in Nature Microbiology.
The study advances the understanding of how Epstein-Barr virus (EBV) and other members of the herpesvirus family enter human cells, said Richard Longnecker, PhD, the Dan and Bertha Spear Research Professor and senior author on the paper.
“This could lead to the development of entry-inhibiting drugs that could be used to prevent infection with herpesviruses or treat people with active infections,” said Longnecker, also a professor of Microbiology-Immunology and a member of the Robert H. Lurie Comprehensive Cancer Center.
Jia Chen, PhD, research assistant professor of Microbiology-Immunology, was first author of the paper, and Xianming Zhang, PhD, research assistant professor of Pediatrics and Bethany Perez-White, PhD, research assistant professor of Dermatology, were also co-authors.
EBV, which commonly causes mononucleosis, is one of nine types of herpesviruses that can infect humans. Others include herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV) and Kaposi sarcoma virus (KSHV).
In humans, EBV infects two types of cells: B cells and epithelial cells; Epithelial cells provide a barrier to that outside world, lining all external surfaces of the human body, while B cells are a type of white blood cell.
Jia Chen, PhD, a postdoctoral fellow in the Longnecker lab, was the first author of the study.
Previous studies have described the entry mechanism for EBV into B cells, largely from the collaborative work of the Longnecker laboratory at Northwestern Medicine, the Jardetzky laboratory at Stanford and the Zhou laboratory at the University of California, Los Angeles. Up until now, however, EBV’s mechanism of entry into epithelial cells was a mystery.
“The key missing piece was the epithelial receptor,” Longnecker said. “Previous studies had suggested the integrins were the entry receptor, but work in our laboratory using CRISPR-Cas9 gene deletion had found integrins were not essential for EBV epithelial cell entry.”
Instead, the Longnecker lab used a novel bioinformatics approach, analyzing gene expression in cells susceptible to EBV infection and cross-referencing it with gene expression in cells resistant to EBV infection. This approach identified EphA2, a protein-encoding gene, as a potential receptor.
Longnecker then used CRISPR to delete EphA2 from epithelial cells, which blocked infection, validating EphA2’s role as an entry receptor. Further, EphA2 is often activated in cancers, raising the possibility it may be involved in early cancer development.
While this study doesn’t instantly chart the entire mechanism of infection, it provides an important jumping-off point for future work, Longnecker said.
“We will continue to investigate the mechanism of EBV infection in epithelial cells, as well as the potential link of EphA2 signaling in epithelial cancer,” Longnecker said.
The study was supported by grant AI076183 from the National Institute of Allergy and Infectious Diseases, by grant CA117794 from the National Cancer Institute, by grant AI119480 from the National Institute of Allergy and Infectious Diseases as well as by the Chicago Biomedical Consortium grants Fall 14-0121 and 15-0257 and the American Cancer Society.
Source:
Adapted (with modifications) from Northwestern Medicine News Center, by Will Doss, posted on January 9, 2018.
Publication attributed to the *CBC funding:
Chen J, Sathiyamoorthy K, Zhang X, Schaller S, Perez White BE, Jardetzky TS, Longnecker R. Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nat Microbiol. 2018 Feb;3(2):172-180. (PubMed)
See also:
CBC Awards:
*CBC PDR Award (2014):
PIs: Jia Chen and Richard Longnecker (NU) for the project:
▸ Identification of small molecule compounds as inhibitors of Epstein-Barr virus infection
*CBC PDR Award (2015; renewal):
PIs: Jia Chen and Richard Longnecker (NU) for the project:
▸ Identification of small molecule compounds as inhibitors of Epstein-Barr virus infection
CBC PDR Award (2014):
PIs: Bethany Perez White and Spiro Getsios (NU) for the project:
▸ Eph Receptor Binding Partners that Regulate Human Epidermal Stem Cell Fate
CBC PDR Award (2015):
PIs: Bethany Perez White and Spiro Getsios (NU) for the project:
▸ Eph Receptor Binding Partners that Regulate Human Epidermal Stem Cell Fate
CBC Catalyst Award (2012):
PIs: Richard Longnecker (NU), Lijun Rong (UIC) and Bernard Roizman, ScD (UChicago) for project:
▸ Genome Wide siRNA Screen for Host Factors Required for Human Herpesvirus (HHV) Latency
CBC Boards:
CBC Scientific Recruitment Board (SRB; 2007-2012):
Richard Longnecker – Member